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Immovilli, P.; Morelli, N.; , .; Rota, E. Multiple Sclerosis Treatment in the COVID-19 Era. Encyclopedia. Available online: https://encyclopedia.pub/entry/22134 (accessed on 12 July 2025).
Immovilli P, Morelli N,  , Rota E. Multiple Sclerosis Treatment in the COVID-19 Era. Encyclopedia. Available at: https://encyclopedia.pub/entry/22134. Accessed July 12, 2025.
Immovilli, Paolo, Nicola Morelli,  , Eugenia Rota. "Multiple Sclerosis Treatment in the COVID-19 Era" Encyclopedia, https://encyclopedia.pub/entry/22134 (accessed July 12, 2025).
Immovilli, P., Morelli, N., , ., & Rota, E. (2022, April 21). Multiple Sclerosis Treatment in the COVID-19 Era. In Encyclopedia. https://encyclopedia.pub/entry/22134
Immovilli, Paolo, et al. "Multiple Sclerosis Treatment in the COVID-19 Era." Encyclopedia. Web. 21 April, 2022.
Multiple Sclerosis Treatment in the COVID-19 Era
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This entry is adapted from the peer-reviewed paper 10.3390/neurolint14020030

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by inflammation and early axonal damage, and it is the leading cause of disability in young adults. MS is a multifactorial disease caused by a complex interplay between genetic and ambiental risk factors. Some genes encoding for immune system components lead to a higher risk of developing MS and other acquired risk factors (vitamin D plasma level, solar light exposition, salt intake, the smoking habit and some infections and so on)

multiple sclerosis COVID-19 SARS-CoV-2 anti-CD20 fingolimod ocrelizumab S1P-modulators DMD MS therapy-related risks vaccination

1. Introduction

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, characterized by inflammation and early axonal damage [1], and it is the leading cause of disability in young adults [2]. MS is a multifactorial disease caused by a complex interplay between genetic and ambiental risk factors. Some genes encoding for immune system components lead to a higher risk of developing MS and other acquired risk factors (vitamin D plasma level, solar light exposition, salt intake, the smoking habit and some infections, etc.) may also increase the risk [3][4][5]. Moreover, it seems that the Epstein–Barr virus infection is a “necessary but not sufficient” factor for the development of MS [6].
MS is characterized by a wide range of motor, behavioral and cognitive symptoms [7], reflecting the “functional systems” involved by inflammation, demyelination and neurodegeneration. Its diagnosis, according to the 2017 revised MacDonald criteria [8], is based on the demonstration of “a dissemination in space and time” of typical multiple sclerosis lesions evidenced by brain and spinal cord magnetic resonance imaging [9][10].
The disease-modifying drugs (DMDs) used to treat MS comprise a range of molecules and monoclonal antibodies, which have a wide spectrum of efficacy and adverse events [11][12][13]. Although most MS DMDs affect the immune system, some of them also affect the neurodegenerative metabolic pathways, for example, the nuclear factor erythroid-2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling, an enzyme involved in the pathogenesis of MS [14].
The coronavirus disease (COVID-19) pandemic has put enormous strain on healthcare organizations, medical resources and emergency medical services [15]. Primary care bears a particularly high burden, and the management of multiple sclerosis (MS) involves reconfiguring patient care so as to take into account specific aspects. Indeed, additional risk factors for severe COVID-19 must be considered for people with multiple sclerosis (pwMS), for example, progressive disease, disability and immunomodulating/suppressive treatment [16]. Moreover, vaccination is not without certain implications for pwMS, in as much as MS treatment may not only interact with the vaccine response, but the vaccine may also have an effect on the MS course. There is a complex interplay between COVID-19 pathogenesis and the psychological consequences of the pandemic. The hallmark of COVID-19 pathogenesis is the cytokine storm, which may lead to severe pneumonia, stroke [17], pulmonary thromboembolism and critical illness. Indeed, COVID-19-associated psychological stress is one of the major consequences of the pandemic and could interact with inflammatory and degenerative processes in the central nervous system [18]. Moreover, COVID-19 fear has been associated with amygdala activation [19], and the resilience to psychological consequences of the pandemic seems to be a crucial factor to prevent negative sequelae [20].
Even neurologists had to face with the fears associated with COVID-19, which led to concerns that modified neurologists’ attitude toward prescribing DMDs [21]. They must now take into account the pros and cons of a severe COVID-19 and the risk of the disability related to MS under-treatment, the risk of a severe COVID-19 and propose the most appropriate vaccination strategy to be used, depending on the treatment regime.
Numerous epidemiological ones have described the risk factors involved in severe COVID-19 in MS patients [22][23][24][25]. Others have investigated the humoral and cellular immune response to vaccines [26][27]. Apart from these, although there are some systematic ones on COVID-19 in MS patients on breakthrough infection in vaccinated MS patients [28], the publications that pool all these aspects aimed at identifying future strategies in the management of pwMS in the COVID-19 era are limited.

2. COVID-19 Mortality

COVID 19 mortality during the pandemic is estimated by the case fatality rate. This rate is highly variable [29] and depends on many factors, some of which can be related to the patient (risk factors for severe COVID-19), to the SARS-CoV-2 virus, and others to the pandemic phase. The factors linked to the patients include age and some diseases (cardiovascular, cerebrovascular, lung, chronic kidney disease, obesity, cancer, immunosuppression and so on). All these factors are under the “umbrella term” severe COVID-19 risk factors. The core issue is whether MS and DMDs are risk factors for pwMS [22][23][24][25].
Variants and mutations are linked to the virus and may determine different infectivity and mortality, depending on the variant. The factors linked to the pandemic phase are the COVID-19 incidence rate and the intensive care unit (ICU) hospitalization rate.
There is an association between mortality and incidence [15] and an inverse association between mortality and the rate between hospitalization in an ICU and/or medical wards [30]. The lockdown reduced social contacts and viral spreading, and the increase in the availability of ICU beds allowed intensive care to be provided to a larger population. Unfortunately, the long-term social costs of these interventions are very high and not sustainable.
Although the COVID-19 crude mortality rate (CDR) for pwMS and the general population did not differ greatly, pwMS are mostly female and young. Therefore, when mortality was corrected for gender and age, it was higher in pwMS, particularly when they had significant disability and a progressive disease course [31]. Furthermore, Prosperini et al. carried out a pooled analysis of cohort studies and reported a 24% increased risk of death from COVID-19 in patients with MS. Additional risk factors for higher mortality were age, comorbidity, a progressive disease course, anti-CD20 therapy; interferon and teriflunomide administration were inversely associated with mortality [32].

3. Severe COVID-19 Risk Factors in pwMS

The most common COVID-19 symptoms in pwMS were asthenia, cough, fever, headache, anosmia, ageusia, dyspnea, digestive disorders and/or dizziness. Cough and dyspnea were more frequently observed in severe situations and headache and anosmia in outpatient one [23]. SARS-CoV-2 infection has a wide range of severity, from asymptomatic infection to fatal acute respiratory distress syndrome (ARDS). Epidemiological ones frequently split the disease severity into a three-level variable: (1) mild-severity disease, characterized by no need for hospitalization and the absence of pneumonia; (2) intermediate-severity disease, characterized by the need for hospitalization and/or the presence of pneumonia; (3) severe COVID-19, characterized by death or ICU admission [22]. The Covisep group described SARS-CoV-2 infection severity with a seven-level variable (the so-called “COVID-19 severity score”) [23], but in a further pooled analysis of French and Italian data, COVID-19 severity was described as a three-level variable [16].
Risk factors for severe COVID-19 were older age, male gender, an Extended Disability Status Scale (EDSS) score of >3, comorbidities (for example, cardiac, obesity and so on), having been administered methylprednisolone in the month before infection, anti-CD20 [16][22][23][24][25] and a progressive MS course. Interferon was associated with a better outcome [32].

4. Vaccine Response in pwMS

DMDs can affect vaccine efficacy in pwMS, as reported by some papers. The first one was published by Achiron et al., who observed a reduced vaccine humoral response in patients on ocrelizumab and fingolimod [33]. Then, the Italian CovaxiMS group reported a reduced humoral response in patients on fingolimod and anti-CD20, and a better vaccination response was associated with higher pre-vaccination antibody levels and the use of mRNA-1273 (Moderna) vaccine. A better humoral response to vaccination was observed in pwMS treated with ocrelizumab when it was inoculated later, after the last ocrelizumab infusion, and higher antibody titers were observed when the lymphocyte count was higher in patients on fingolimod [34].
Others investigated the T-cell immune response and the humoral response together after vaccination, observing a reduction in both responses during fingolimod treatment and a reduction in humoral response along with an enhancement in T-cell response during anti-CD20 therapy [26][27].
The immune response to SARS-CoV-2 infection in pwMS treated with DMDs was similar to the vaccine response, for example, the cellular response was still present at 13 months after COVID-19 in 59.5%, and the humoral response persisted up to 6 months in 81.1%. Patients on treatment with anti-CD20 had a lower antibody response, but severe COVID-19 and a longer time lapse since the last infusion was associated with a better humoral response. There was a cellular response in all the treatment groups [35]. Immune T-cell response to vaccination seems to be more important than antibodies in terms of prevention of death, hospitalization and severe COVID-19 [36].
Some are reported a better vaccine response in pwMS on anti-CD20 treatment who did not have a complete B-cell depletion at vaccination, and there was a better response in pwMS treated with S1P modulators in the presence of a high lymphocyte count [37].

5. The Effects of Vaccines on MS

Di Filippo and Achiron investigated the relapse risk after Pfizer/BioNTech BNT162b2 vaccine in an Italian and Israeli cohort, reporting no increased risk of relapse activity [38][39]. However, there are some pwMS who had relapses after SARS-CoV-2 vaccination. Noteworthy is the series reported by Nistri et al., where there was a temporal association between vaccination and MS relapses, although the design made it impossible to establish whether this association was incidental or causative [40]. In this complex interplay between immune system stimulation and relapse risk, it must not be forgotten that single situation of MS relapses after COVID-19 have also been reported [41].

6. Breakthrough Infection

Research investigating the risk of COVID 19 in vaccinated pwMS treated with DMDs is ongoing, and the Italian CovaXiMS group published a pre-print reporting an association between low specific SARS-CoV-2 antibody titers and the risk of SARS-CoV-2 breakthrough infection [28]. The French COVISEP group described 18 cases of breakthrough infections; 13/18 were treated with antiCD-20, but only 1/13 was hospitalized for non-invasive mechanical ventilation. These findings are consistent with an increased risk of breakthrough infection but not for severe COVID-19 in pwMS vaccinated during anti-CD20 treatment [42].

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Paolo Immovilli
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Nicola Morelli
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Eugenia Rota
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Update Date: 22 Apr 2022
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